Diffuse Axonal Injury in Periventricular Leukomalacia as Determined by Apoptotic Marker Fractin

Abstract

Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [␤-amyloid precursor protein (␤-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using ␤-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage. (Pediatr Res 63: 656-661, 2008)

Neurotransmitter signaling in white matter

“…Injury to WM as a consequence of hypoxic-ischemic injury occurs in periventricular leukomalacia (PVL) in neonates and in stroke and cardiac arrest in adults, as well as in vascular dementia in the aging brain. The metabolic rate of WM is only modestly lower than that of GM, and animal studies suggest that WM can be damaged by even brief ischemia (Pantoni et al, 1996) Ischemic injury to axons is also a feature of PVL; it occurs early in local and diffuse damage associated with this pathology (Haynes et al, 2008). Interestingly, experimental ischemia in immature axons produces action potential failure and focal breakdown of the axolemma of small premyelinated axons at sites of contact with oligodendrocytic processes, which are also disrupted (Alix and Fern 2009).…”

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

“…Axonal degeneration is a common feature of necrotic WMI and can be detected both within and distal to large necrotic foci [124]. Whether primary axonal injury occurs in cases of typical macroscopic necrotic lesion defined by diffuse dense staining for reactive microglia and macrophages with Iba1 (red; inset) and a paucity of GFAP-labeled astrocytes.…”

Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic field

“…PVL has been associated with coagulation necrosis in the white matter adjacent to the external angle of ventricles, preoligodendrocyte death, microglial activation, and astrogliosis (8). Recently, apoptosis in the white matter as well as basal ganglia injury and associated cortical injury have been characterized in the preterm brain (9)(10)(11).…”